Abstract: Trauma, stroke, and neurodegenerative disease result in neuronal loss, which leads to morbidity and mortality. A major advancement to mitigate these conditions would be to harness the ability to regenerate lost neurons. Although neural stem cells (NSCs) and neurogenesis normally exist in adult brain, the scarcity and restricted localization render them inadequate for regeneration. Cell transplantation is currently the strategy of choice to deliver new neuronal cells, but this approach is inefficient and cumbersome due to limited cell survival and poor integration into the functional neural networks following transplantation. In a highly novel approach to adult neurogenesis studies based on recent findings, we hypothesize that endogenous glial cells can be directly converted into neurogenic NSCs so that de novo-generated neurons will repopulate damaged brain regions. This hypothesis is based on our extensive studies using an essential nuclear receptor for NSCs and on the recent advancement of induced pluripotent stem (iPS) cells. We previously revealed that nuclear receptor TLX is not only essential for adult neurogenesis but is also sufficient to convert differentiated astrocytes into NSCs in culture. Although somatic cells from various tissues can be reprogrammed to iPS cells, it is not clear whether somatic cells can also be directly induced to form NSCs and neurons. Through transcriptional reprogramming, we propose to convert astrocytes and microglia, the two most proliferative glia cells during CNS damage, into NSCs and neurons. Using regulated expression of TLX in cultured cells and in transgenic mice, we will induce astrocytes to become proliferative, multipotent NSCs and then differentiate them into neurons. In addition, by using combinations of transcription factors, we will directly reprogram astrocytes or microglia to NSCs in cell culture and in adult mouse brains. Our long-term goal is to repopulate the damaged CNS regions using the patient's endogenous non-neuronal cells. Public Health Relevance: Trauma, stroke or degeneration can result in permanent damage to the central nervous system (CNS), which leads to disability and mortality. Currently, care and treatment of patients with CNS injury are demanding and extremely expensive. Our proposed research focuses on adult neurogenesis and takes an innovative approach to induce the production of new neurons in the adult CNS, with the ultimate goal of repairing the function of damaged CNS using endogenous cells from patients. Thus, our research is highly relevant and significant to public health.